Transmissible spongiform encephalopathies (TSEs or prion disease) are fatal neurodegenerative diseases such as scrapie, Creutzfeldt-Jakob disease (CJD), BSE and chronic wasting disease (CWD). Our project is aimed at understanding and blocking the accumulation of PrP-res, the abnormal form of prion protein (PrP) that appears to underlie TSE transmission and pathogenesis. Using animal models, cell culture and cell-free systems we have 1) identified the curry spice curcumin as a potent and edible new inhibitor of PrP-res formation, 2) compared the in vivo anti-scrapie effects of deuteroporphyrins containing different divalent metal ions, 3) determined that reshuffling of the disulfide bonds in PrP-res is not necessary for PrP-res formation, 4) established cellular models of acute scrapie infection and PrP-res formation using scrapie brain microsomes as sources of infectivity, 5) determined that normal PrP and PrP-res do not interact efficiently unless they are in the same membrane, 6) analyzed the role of helix 1 salt bridges in PrP-res formation, 7) developed solid phase conversion assays in an effort to develop high-throughput screens for potential anti-TSE drugs, 8) further characterized regions of PrP-res that are differently folded as a function of TSE strain, and 9) begun to assess the role of PrP in the heart by looking for differences in resistance of wild-type and PrP knockout mice to ischemia-reperfusion injury.